Project Summary APOE4 is the strongest genetic risk factor for Alzheimer?s Disease (AD) and obesity is one of the most common environmental risk factors for AD. With 14% of the population being APOE4 carriers and 30% of the population suffering from obesity, it is extremely important to understand how these two common AD risk factors interact. We will analyze these interactions in healthy rodent models. Previous studies in mice have shown the combination of obesity and APOE4 further exacerbates AD pathology and cognitive decline; the studies proposed here aim at understanding alterations that occur before AD onset. APOE3 and APOE4 knock-in mice were placed on high fat ?western? diets (HFD, 45% fat) for 12 weeks starting at 6 months old. Aim 1a examined the metabolic and cognitive disturbances associated with HFD and we found HFD increased metabolic disturbances in APOE3 and APOE4 mice, with APOE4 mice being more susceptible. Aim 1b examined effects of HFD on glial immunoreactivity, lipid droplet accumulation, and neuronal complexity. We found HFD increased glia immunoreactivity and lipid droplet (LD) accumulation in APOE3 and APOE4 mice. The remainder of my thesis will focus on identifying mechanisms underlying glia immunoreactivity and LD accumulation and reducing HFD induced alterations. Aim 2a will examine parallel peripheral metabolic and inflammatory pathways induced by HFD. We will investigate: 1) With HFD, are specific inflammatory or metabolic genes altered? 2) Is there a correlation between the specific genes altered in the periphery and CNS with HFD? 3) Do the specific genes altered by HFD differ between APOE3 and APOE4 genotypes? Aim 2b will examine whether LD composition differs between genotypes and diets, and if increases in LD accumulation is associated with oxidative stress. We will investigate: 1) Does LD composition differ between APOE genotype and diet? 2) Does LD accumulation correlate with increased oxidative stress? 3) Do LDs colocalize with reactive oxygen species? Aim 2c will examine whether Metformin will ameliorate the LD accumulation and gliosis associated with HFD. We will investigate: 1) Does Metformin reduce gliosis and LD accumulation? 2) Do LDs co-localize with microglia or astrocytes? After completing my PhD, I will continue to build skills in a post-doctoral setting researching the mechanisms underlying diet induced cognitive alterations through metabolomics and transcriptomics. I will be successful in this through first identifying an ideal post-doctoral lab then obtaining the post-doctoral position. My goal is to complete my post-doctoral fellowship at an institution that values rigorous scientific research, innovation, training and professional development. To obtain this fellowship, my sponsor and I have committed to a plan that includes identifying an ideal lab setting. We have agreed to working with my committee members and collaborators, attending multiple conferences and networking events, and inviting speakers. The F99/K00 will greatly assist me in both completing my PhD and obtaining the postdoctoral position I am striving for.